1. Field of the Invention
The present invention provides compositions, medicaments and methods for the prevention or prophylaxis of dental caries and infective endocarditis.
2. Description of the State of the Art
Dental caries is an undesirable condition of the oral cavity and, over the years, has remained an intractable disease. Caries is a unique multifactorial infectious disease. (Lenander-Lumikari et al., Adv. Dent. Res. 14: 40–47 (December 2000)). Dental caries affects teeth at all levels and can cause extensive crown mutilations, bacterial disorders of the periapical tissues, or even loss of the affected dental elements. Clinically, the disease is characterized by demineralization of the dental enamel and of the dentin in various stages of progress until it affects the pulp space. When the lesion passes beyond the enamel-dentin border, a phlogistic reaction of the pulp tissues is constantly observed, with the formation of reaction dentin in some cases. Approximately 50% of adults have at least four caries-related lesions that have been treated or require treatment, and approximately 30% of adults have over 50% of their teeth affected by caries. With advances in science and technology, newer methods have been introduced to combat this disease but the search for an acceptable treatment continues.
Efforts toward the correction of dental caries have revolved around the use of the standard toothbrush to remove dental plaque. Also in widespread use today are electric brushes, floss and adjuncts such as proxy brushes. In addition, numerous toothpastes and mouth rinses containing various supplements that are touted as aids in the prevention of dental caries. For example, fluoride is commonly sold as a product for slowing the process of dental decay. However, the efficacy of such methods of treating or preventing dental caries is questionable. Dental plaque can only partially be removed from the oral cavity, even when a demanding regimen of oral hygiene that may include flossing, brushing and regular visits to a dentist is followed. In addition, many toothpastes and mouth rinses contain toxic supplements such as fluoride and triclosan that can be toxic to very young children. Further, most oral bacteria are benign and are actually important for oral health. Consequently, an overall reduction in oral bacteria is not a practical means to prevent tooth decay. For example, when the level of certain oral bacteria is reduced (e.g., after prolonged use of antibiotics), an overgrowth of indigenous yeast occurs, resulting in a disorder known as Thrush.
In the last half century, it has become clear that dental plaque actually consists of hundreds of different bacterial taxa. Most of these bacteria exist on the surface of teeth in heterogeneous communities called plaque or biofilms. The mouth thus acts as a reservoir for these bacteria. While most of these bacteria are commensal, meaning they fail to adversely affect the human host, others are pathogenic and can cause tooth decay. Moreover these pathogenic bacteria have been found to cause a life-threatening disease called endocarditis.
Among all of these bacteria, the primary etiologic agent of tooth decay is the bacterium Streptococcus mutans. S. mutans is a resident of the biofilm environment of dental plaque, a matrix of bacteria and extracellular material that adheres to the tooth surface. Under appropriate environmental conditions populations of S. mutans and the pH of the surrounding plaque will drop. S. mutans, being among the most acid tolerant organisms residing in dental plaque, will increase it numbers in this acidic environment and eventually become a dominant member of the plaque community. Once attached, S. mutans inflicts its damage by fermenting simple dietary sugars into lactic acid. This situation eventually leads to dissolution of the tooth enamel, resulting in the development of dental caries. Since there is a strong correlation between the proportion of S. mutans in dental plaque or in saliva relative to other bacterial species and the presence or risk of future outbreaks of dental caries, S. mutans in plaque or saliva may serve as an index for both caries activity state and caries risk or susceptibility. These indices play an increasingly important role in the diagnosis and treatment of dental caries. (Hume, W. R., J. Dent. Educ. 57: 439–443 (1993)).
S. mutans has also been found to contribute to infective endocarditis. Infective endocarditis is a potentially lethal infection of both native (normal) and artificial heart valves, and if left untreated can be fatal. S. mutans form biofilms on the surface of these valves, and are typically a mixed community of a variety of pathogenic bacteria. Since the these bacteria find their way to the valves via the blood stream and the blood stream is typically aseptic, there are usually few opportunities for bacteria to cause these infections. One exception is when pathogenic bacteria like S. mutans enter the blood stream during dental procedures. Hence, the probability of infection is directly related to the reservoir of infectious bacteria found in the oral cavity.
Since S. mutans are recalcitrant to antibiotic therapy in the biofilm phase, preventive approaches are considered safer and more practical. Currently, this approach relies mainly on prophylactic antibiotic therapy in high-risk patients. However, such treatments merely control the spreading of free bacteria (planktonic) and acute infections. Hence, the infections tend to be persistent, requiring multiple rounds of treatments to avoid permanent and lethal valve damage. Therefore, there exists a need for safer prophylactic approaches without the consequences of antibiotic therapy.
Competence Stimulating Peptide (CSP) is a natural peptide produced and secreted by S. mutans and acts as an autoinducer (Li, Y-H et al., J. Bact. 183:897–908 (2001). Competitive inhibitors of CSP have been investigated in relation to a method for the treatment of caries. Specifically, compounds that competitively inhibit the binding of CSP to S. mutans histidine kinase have been studied. (see U.S. Patent Application Publication No. 2002/0081302, which incorporated herein by reference). CSP is specific for S. mutans and functions exclusively as a regulator of many genes such as gtfB and gtfC and leads to repression of gtfB and gtfC gene expression. Glucosyltransferases (GTFs) are the products of these genes and are essential for efficient attachment of S. mutans to the surface of teeth. In the presence of their substrate (sucrose), GTFs catalyze the formation of long polymers of glucose called glucans, which are instrumental in the adherence of S. mutans to the surface of teeth. Once attachment is completed, the gtf genes are repressed and sucrose is utilized as energy source. The catabolism of sucrose results in the production of lactic acid that damages the tooth enamel and cause caries. The concentration of CSP is not naturally produced in significant quantities during the initial attachment to the tooth but is otherwise present after the adhesion is completed to ensure that gtfB and gtfC are repressed.
Since there is a strong association between the number of S. mutans in the oral cavity and the predisposition for tooth decay and endocarditis, a composition that can reduce the efficiency of S. mutans adherence should reduce or even eliminate the dental caries and endocarditis. Moreover, since early colonizing non-pathogenic oral bacteria rely on their own gtf genes for efficient adherence but are not affected by the presence of the S. mutans CSP, such bacteria will gain a competitive advantage over S. mutans if the ability of S. mutans to adhere to tooth surfaces is reduced